T cells in resolved allergic contact dermatitis steer tissue inflammation and <scp>MMP</scp>‐12–driven tissue modulation
Authors: Irène Gallais Sérézal, Poojabahen Tajpara, Trine Schonfeldt, Borislav Ignatov, Daniel Sortebech, Elena Hoffer, Tianqi Zhang, Elin Rooijackers, Marcus Ehrström, Susanne Nylén, Míhaly Matura, Keira Melican, Liv Eidsmo
Journal: Allergy (2022)

Tissue resident memory T cells contribute to localized immunity in barrier tissues such as the skin1 but are also implicated in local relapse of focal inflammatory skin diseases, including allergic contact dermatitis (ACD) and psoriasis.2-4 To investigate how activation of skin T cells initiates relapsing contact dermatitis, global tissue responses to pan-T-cell activation in skin biopsies from methylisothiazolinone (MI)-induced ACD were mapped. Skin biopsies were collected during inflammation, 2 months, and 2 years after resolution of disease (Appendix S1). Despite macroscopic and microscopic disease-resolution (Figure 1A), genes involved in keratinocyte differentiation and antimicrobial responses remained overexpressed for up to 2 years (Figure 1B,C, Figure S1) and resolved epidermis contained a two-fold increase of T cells compared to non-lesional sites (Figure 1D). To model allergen challenge, skin biopsies from patients with lesional or resolved ACD were stimulated with the allergen MI, the pan-T-cell agonist OKT-3 or isotype control for 18 h ex vivo (Figure 1E). Epidermal gene expression analysis highlighted the upregulation of genes involved in ACD pathology in resolved biopsies (Figure 1F). Gene ontology pathway analysis of the epidermal transcriptome identified the involvement of several pathways related to T-cell activation in response to MI and/or OKT-3 (Figure 1G). Inflammatory transcripts that were highly expressed in lesional ACD (Figure 1B), including CXCL10, IL22, and MMP12, were induced by both MI and OKT-3 in biopsies up to 2 years after resolution of ACD (Figure 1F,G). In line with the transcriptome data, MI triggered release of pro-inflammatory cytokines and chemokines in resolved samples (Figure 1H). Following elicitation of ACD, the development of spongiotic pathology and macroscopic dermatitis requires influx of newly recruited immune cells to the epidermis. In addition to chemotactic signals, tissue remodeling and collagen degradation are crucial to facilitate cellular movements through the skin (Figure 2A). The transcript of the metalloproteinase (MMP)-12 is overexpressed in de novo–induced ACD lesions in sensitized skin5 (Figure 2B). In a murine model of ACD, knocking out mmp12 led to reduced skin inflammation.6, 7 We found that MMP12 was upregulated in resolved skin following both MI and OKT-3 stimulation (Figures 1B,F,G and 2C). MMP-12 cleaves collagen I and collagen IV (Figure 2D), one major component of the basement membrane that separates epidermis from dermis. In response to the exposure to ACD-related cytokines: IFNγ, TNF, and IL-17, MMP12 were induced, and MMP-12 was released by primary fibroblasts and keratinocytes (Figure 2E–H), indicating that T-cell activation initiate down-stream function of stroma cells. Considering the collagen IV-degrading capacity of MMP-12 (Figure 2D), and the loss of basement integrity in lesional but not resolved ACD (Figure 2A), we directly tested the impact of MMP-12 on basement membrane integrity and T-cell transmigration between the skin compartments. Explants of full thickness healthy human skin were injected intradermally with MMP-12, TNF, IL-17A, and IFNγ, or control (Figure 2I). MMP-12 alone and in combination with cytokines induced local mobilization and accumulation of T cells in dermis (Figure 2J). Proliferating T cells could not be detected by Ki-67-staining (not shown). Lastly, intradermal injections of MMP-12 and ACD-associated cytokines in human skin xenotransplanted onto SCID-beige mice in vivo8 resulted in degradation of the basement membrane separating the epidermis and dermis, induced local accumulation of T cells and initiated spongiotic pathology (Figure 2K–N). Our data highlight that allergen-driven contact dermatitis has a long-term impact on the transcriptome and local pool of T cells in resolved lesions. Both pan-T-cell activation and allergen challenge induced molecular signs of ACD-like inflammation 2 months and 2 years after disease resolution. Activation of resident T cells in resolved ACD induced signals from cytokines capable of activating the stroma to produce MMP-12, thereby driving tissue remodeling and pathology (Figure 2O). Pathogenic T cells in ACD thus ignites recurrent and disease-specific pathology, and limiting their local persistence is a potential aim of future immunomodulatory treatments. We thank Ning Xu Landén and Angèle Soria for scientific discussion and feedback, Scott Brown for his participation in the data analysis of a previous version of this manuscript, Maria Lagrelius for her help in recruiting patients. Emma Wadman, Kerem Yazar, the medical and paramedical staff of the dermatology department of Karolinska University Hospital, the Occupational and Environmental Medicine Stockholm County Council, for their assistance in recruiting and sampling the patients. LE acknowledge support from Leo Foundation, Karolinska Institutet, KID, Marianne and Marcus Wallenberg Stiftelse, Psoriasisfonden, Hudfonder, Ragnar Söderbergs Stiftelse. KM, TZ acknowledge support from AIMES - Center for the Advancement of Integrated Medical and Engineering Sciences (www.aimes.se) at Karolinska Institutet (1-249/2019) and KTH Royal Institute of Technology (VF-2019-0110), Getinge AB (4-1599/2018), KID (2019-00917) and Swedish Research Council (2020-01790). The authors report no conflict-of-interest linked to this manuscript. Figure S1 Appendix S1 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.